Taming Chiral Quaternary Stereocenters via Remote H-Bonding Stereoinduction in Palladium-Catalyzed (3+2) Cycloadditions.

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol.

Concise Total Synthesis of Salimabromide.

We achieved a concise total synthesis of salimabromide by using a novel intramolecular radical cyclization to simultaneously construct the unique benzo-fused [4.3.1] carbon skeleton and the vicinal quaternary stereocenters. Other notable transformations include a tandem Michael/Mukaiyama aldol reaction to introduce most of the molecule's structural elements, along with hidden information for late-stage transformations, an intriguing tandem oxidative cyclization of a diene to form the bridged butyrolactone and enone moieties spontaneously, and a highly enantioselective hydrogenation of a cycloheptenone derivative (97% ee) that paved the way for the asymmetric synthesis of salimabromide.

Concise Enantioselective Total Synthesis of Daphenylline Enabled by an Intramolecular Oxidative Dearomatization.

Daphenylline is a structurally unique member of the triterpenoid Daphniphyllum natural alkaloids, which exhibit intriguing biological activities. Six total syntheses have been reported, five of which utilize aromatization approaches. Herein, we report a concise protecting-group-free total synthesis by means of a novel intramolecular oxidative dearomatization reaction, which concurrently generates the critical seven-membered ring and the quaternary-containing vicinal stereocenters. Other notable transformations include a tandem reductive amination/amidation double cyclization reaction, to assemble the cage-like architecture, and installation of the other two chiral stereocenters via a highly enantioselective rhodium-catalyzed challenging hydrogenation of the diene intermediate (90% e.e.) and an unprecedented remote acid-directed Mukaiyama-Michael reaction of the complex benzofused cyclohexanone (13:1 d.r.).

Optically Active Flavaglines-Inspired Molecules by a Palladium-Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation.

With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved with high efficiency [0.2-1.0 mol% Pd2(dba)3/L], good generality, and high enantioselectivity (>30 examples, 82-99% yield and 90-96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features a reliable and scalable sequence of the freshly developed Tsuji-Trost-Stoltz AAA, a Wacker-Grubbs-Stoltz oxidation, an intra-benzoin condensation, and a conjugate addition, which allows the efficient construction of the challenging and compact cyclopenta[b]benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-based drugs.

Synthesis of (+)-7,20-Diisocyanoadociane and Liver-Stage Antiplasmodial Activity of the Isocyanoterpene Class.

7,20-Diisocyanoadociane, a scarce marine metabolite with potent antimalarial activity, was synthesized as a single enantiomer in 13 steps from simple building blocks (17 linear steps). Chemical synthesis enabled identification of isocyanoterpene antiplasmodial activity against liver-stage parasites, which suggested that inhibition of heme detoxification does not exclusively underlie the mechanism of action of this class.

Paleo-soraphens: chemical total syntheses and biological studies.

The soraphens are natural products that exhibit a molecular structure different from what would have been expected by following its polyketidal assembly line. The most significant differences are the presence of a hemiketal instead of a trisubstituted double bond and a double bond at C9 and C10 where a saturated carbon chain was expected. We were interested in the biological activity of the soraphens with architectures as described by the polyketide synthase since we hypothesized that these modifications reflect the evolutionary optimization of the soraphens. Herein we describe four additional derivatives of the so-called paleo-soraphens and their biological profiling to provide a picture of the hypothetical evolutionary optimization of this family of natural products. The syntheses required a unified and convergent strategy and their biological profiling was performed with the aid of impedance measurements. The results of these biological experiments are consistent with the proposed evolutionary optimization of the soraphens.

The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis.

The vinylogous Mukaiyama aldol reaction (VMAR) allows efficient access to larger segments for complex natural product synthesis, primarily polyketides, through the construction of vicinal hydroxyl and methyl groups as well as di and tri-substituted double bonds in one single operation. In this review, we will highlight stereoselective protocols that have been used in natural product synthesis and cluster them into the four groups that can be obtained from different silyl ketene acetals or enol ethers. At the beginning, an overview on different stereoselective VMARs is presented; disregarding their applications in total syntheses.

Synthesis and biological evaluation of paleo-soraphens.

Synthesis can provide molecules such as paleo-soraphens A and B that are genetically encoded but not obtained from the natural source. Although it is unclear whether this is part of an evolutionary process or the consequence of the chemical synthesis, the biological evaluation of these genetically encoded natural products can shed light on how natural products are structurally optimized with respect to their biological profile.

Catalytic asymmetric intramolecular hydroarylations of omega-aryloxy- and arylamino-tethered alpha,beta-unsaturated aldehydes.

Economical approach: The first organocatalytic asymmetric intramolecular hydroarylation of phenol- and aniline-derived enals offers one of the most straightforward and atom-economic approaches to enantioriched chromans and tetrahydroquinolines (up to 96% ee; see scheme).

Highly enantioselective organocatalytic Michael addition of nitroalkanes to 4-oxo-enoates.

A useful Michael addition reaction using nitroalkanes as the nucleophile and 4-oxo-enoates as the Michael acceptor has been disclosed, and the reaction allows expedient access to functionalized chiral gamma-keto esters in high yields and excellent enantioselectivities (up to 98% ee), with a low catalyst loading.

Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies.

The 'neurotrophic sesquiterpenes' refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other 'cage convulsant' compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.

[A study of the clinical classification of 3638 cases of mushroom poisoning].

OBJECTIVE: To study the clinical classification and characteristics as well as prognosis of mushroom poisoning. METHODS: We retrospectively analyzed 191 papers published domestically for 3466 cases of mushroom poisoning from 1995 to 2004 and studied the Xinqiao Hospital data of 172 cases of mushroom poisoning treated from 1980 through 2004. We made a retrospective investigation and clinical classification of all the 3638 cases of mushroom poisoning. RESULTS: Among the 3638 patients, clinical manifestations as gastroenteritis were found in 571, all of them were cured. The most common symptoms were those of acute renal failure being found in 1450 cases; 1414 were cases (97.5%) and 36 died (2.5%). Symptoms of toxic hepatitis were found in 1010 cases, 841 were cases (83.3%) and 169 died (16.7%). Psychoneurological disorder was manifested in 214 cases; 197 were cases (92.1%) and 17 died (7.9%). Erythrolysis was found in 73 cases; 71 were cases (97.3%) and 2 died (2.7%). The therapeutic effect and prognosis of mushroom poisoning with different clinical manifestation varied very significantly (P < 0.001). Of the 320 cases clinically unclassified, multiple organ dysfunction syndrome was found in 222 cases; 98 were cases (44.1%) and 124 died (55.9%). Definite classification could not be made in 98 cases; 90 were cases (91.8%) and 8 died (8.2%). CONCLUSIONS: The clinical classification of mushroom poisoning was usually of four types as described in the textbooks or special articles, but it should be of five types according to the analysis of the data of the present study, i.e. gastroenteritis type, acute renal failure type, toxic hepatitis type, psychoneurological disorder type and erythrolysis type. It is not clear whether there is a mixed type or not. Further investigation is needed in this respect.

[Committed differentiation of transplanted bone derived mesenchymal stem cells and their potential to amend damaged liver functions: in vivo experiment with mice].

OBJECTIVE: To observe whether bone mesenchymal stem cells (MSCs) have the potential to transdifferentiate into functional hepatocyte-like cells in the special "niche" as well as the therapeutic feasibility to repair damaged liver in mice. METHODS: 20 nude mice were randomly divided into four groups (n = 5 in each group): Group A: 1.0 ml/kg of carbon tetrachloride (CCl(4)) (dissolved in olive oil by ratio of 1:1) was injected into the peritoneum of mice twice a week for 5 weeks. GFP-positive MSCs (1 x 10(6) cells) were injected into the caudal tail vein 1 week after the first dose of CCl(4); Group B: treated with CCl(4) as in A, but received the same volume of saline; Group C: normal nude mice with GFP-positive MSCs Transplanted in the same way as in A. Group D: normal controls. 4 weeks after the cell transplantation, all animal subjects were killed. Liver function tests (LFT), histology of HE and Masson staining as well as double immunofluorescent staining for GFP and albumin were studied in all groups. RESULTS: The hepatic fibrosis in group A & B confirmed the success of model for liver damage and there was no marked difference in the percent of the area occupied by collagen between two groups (10.5 +/- 1.5 vs 12.7 +/- 1.6, t = -2.238, P > 0.05). GFP-positive MSCs were mainly observed around portal area or interspace of lobules in group A. Some of GFP-positive cells also express albumin (35% +/- 7%). While in group B, C or D, there is no such findings. The level of serum albumin in group A was higher than that in group B (24.4 g/L +/- 3.3 g/L vs 18.6 g/L +/- 2.9 g/L, P < 0.05) while the level of ALT was also different between two groups (121 U/L +/- 21 U/L vs 192 U/L +/- 29 U/L, P < 0.05). CONCLUSION: The stimulus of persistent liver damage might enhances the migration of MSCs to the liver, in which some of the MSCs have the potential to transdifferentiate into hepatocyte-like cells. Transplantation of MSCs might amend the damaged tissue of host liver to a certain extent.

Readily tunable and bifunctional L-prolinamide derivatives: design and application in the direct enantioselective Aldol reactions.

[reaction: see text] Readily tunable and bifunctional L-prolinamides as novel organocatalysts have been developed, and their catalytic activities were evaluated in the direct asymmetric Aldol reactions of various aromatic aldehydes and cyclohexanone. High isolated yields (up to 94%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) were obtained under the optimal conditions.

An eight-step gram-scale synthesis of (-)-jiadifenolide.

Development of a biologically active secondary metabolite into a useful medicine requires continuous access to meaningful quantities of material. Although any chemical synthesis is broadly useful for its versatility, identification of a synthesis route that can be economically scaled represents a greater challenge. Here we report a concise synthesis of the neurotrophic trace metabolite (-)-jiadifenolide and its production on a gram-scale. The brevity of the route and the structural similarity of a key intermediate to many potent Illicium terpenes make chemical synthesis the unquestionable method for accessing and modifying these potential therapeutics.

Enantioselective conjugate addition of oximes to trisubstituted ß-nitroacrylates: an organocatalytic approach to ß(2,2)-amino acid derivatives.

A highly enantioselective organocatalytic intermolecular conjugate addition of oximes to ß-nitroacrylates has been developed. The highly functionalized adducts obtained are valuable precursors for asymmetric synthesis, as demonstrated by the synthesis of ß(2,2)-amino acids and oxazolidin-2-ones.

Enantioselective Michael reactions of beta, beta-disubstituted nitroalkenes: a new approach to beta(2,2)-amino acids with hetero-quaternary stereocenters.

An atom-economic organocatalytic asymmetric Michael reaction of alpha,beta,beta-trisubstituted olefins has been successfully developed. The reaction exhibits excellent enantioselectivities under low loading of catalysts, and the conjugate addition products are valuable for the synthesis of novel beta(2,2)-amino acids and beta-peptides.